Painful neuropathy is the principal dose-limiting factor requiring discontinuation of chemotherapy with vincristine, taxol and cisplatin, the frontline chemotherapeutic drugs used for a multitude of tumors, including leukemia, lung, and breast cancers, those most common in Americans. Moreover, this pain is refractory to treatment and often persists in cancer survivors. The long-term goal of this project is to determine the mechanism of chemotherapy-induced pain and identify potential therapeutic interventions for its relief and prevention. Three hypotheses related to this goal will be tested in three specific aims that are composed of complementary studies in humans who have received or are undergoing chemotherapy with vincristine, taxol or cisplatin and in animals treated with the same compounds. Hypothesis 1: Vincristine, taxol and cisplatin have shared effects on primary afferent fiber function that contribute to neuropathic pain. This hypothesis will be tested in humans alone. Specific Aim 1.1: Primary afferent function will be tracked by quantitative sensory testing over time during chemotherapy in cancer patients. The results in patients who develop pain will be contrasted with those in normal volunteers and with data from patients who do not develop pain. Hypothesis 2: Vincristine, taxol and cisplatin have shared effects on pro-inflammatory cytokines that contribute to neuropathic pain. This hypothesis will be tested in humans and animals. Specific Aim 2.1: Blood serum levels of cytokines, quantitative sensory function and symptom assessments will be tracked over time in patients as they undergo chemotherapy. The results in patients who develop pain will be contrasted to normative controls and to patients who do not develop pain. Specific Aim 2.2: In animals, the expression of cytokines in blood serum, spinal cord, dorsal root ganglia, and plantar skin will be measured over time with chemotherapy. Hypothesis 3: Chemotherapy-induced neuropathy is produced by the action of proinflammatory cytokines in specific body compartments. This will be tested in animals alone. Specific Aim 3.1: Individual cytokines shown to be elevated by chemotherapy will be infused onto spinal cord, dorsal root ganglia and around nerve endings in skin to reproduce the behavioral signs of chemo-neuropathy. Specific Aim 3.2: Cytokine antagonists will be administered systemically and into local body compartments in parallel with the chemotherapeutic drugs to prevent the onset of chemo-neuropathy. In summary this project will define mechanisms of chemotherapy-induced pain, identify novel near-term treatment candidates, and establish the key databases needed to design and justify follow-up clinical trials. This project will therefore improve the quality of life, survival and return to productivity of hundreds of thousands of patients that are affected by this neuropathy each year.